JP2606275B2 - Optically active benzenecarboxylic acids and their production - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a compound represented by the general formula (I): (Wherein, R represents an alkyl group or an alkoxyalkyl group which may contain a halogen atom having 1 to 20 carbon atoms,
n is 1 or 2, and * represents an asymmetric carbon atom. The present invention relates to an optically active benzenecarboxylic acid represented by the formula and a method for producing the same.

<Prior Art> The optically active benzenecarboxylic acids represented by the above general formula (I) are novel compounds which have not been described in any literature, and their production methods have been known as well as their usefulness as compounds. Not.

<Problems to be Solved by the Invention> The optically active benzene carboxylic acids represented by the general formula (I) are also useful as intermediates for pharmaceuticals, agricultural chemicals, etc., but are especially organic electronic materials, especially intermediates for novel liquid crystal compounds. Very useful as.

For example, the optically active benzenecarboxylic acids can be led to a novel liquid crystal compound by a method represented by the following formula, and the compound has very excellent properties as a ferroelectric liquid crystal.

(In the formula, Ar represents an aromatic group, R represents an alkyl group or an alkoxyl group, and 1 is 1 or 2. R, n, and * have the same meanings as described above.) Means for the present invention> The present invention, of course,
An object of the present invention is to provide an optically active benzenecarboxylic acid represented by the general formula (I), which is a novel compound useful as an intermediate of an organic electronic material, especially a liquid crystal compound.

The present invention relates to the following: [First Step] General Formula (II) (Wherein R ′ represents a lower alkyl group, a lower alkoxyl group or a benzyl group which may be substituted with a halogen atom; n is 1 or 2). And the general formula (III) Wherein R ′ represents a lower alkyl group, a lower alkoxyl group or a benzyl group which may be substituted with a halogen atom, and n is 1 or 2. [Second step] The alcohol represented by the general formula (III) obtained in the first step is reacted with an acetic acid derivative to produce a compound of the general formula (IV) Wherein R ′ and n have the same meaning as described above, and R ″ represents a methyl group. [Third Step] [Third Step] The general formula (IV) obtained in the second step Is asymmetrically hydrolyzed using an esterase having the ability to hydrolyze one of the optically active forms of the ester represented by the general formula (V) (Wherein, R ′ and n have the same meaning as described above, and the asterisk denotes an asymmetric carbon atom). Step of Obtaining Optically Active Alcohols [Fourth Step] The obtained optically active alcohol represented by the general formula (V) is converted to a compound represented by the general formula (VI): R-COOH (VI) (wherein R is an alkyl which may contain a halogen atom having 1 to 20 carbon atoms) Or an alkoxyalkyl group) to react with an aliphatic carboxylic acid of the formula (Wherein, R, R ′, n and * have the same meanings as described above) [Step 5] [Step 5] In the general formula (VII) obtained in the step 4, In the step of debenzylating the shown optically active ester derivative to obtain the optically active benzenecarboxylic acid represented by the general formula (I), the first to fifth steps and the second to fifth steps are respectively performed.
This is a method for producing an optically active benzenecarboxylic acid represented by the general formula (I), comprising a step, third to fifth steps, fourth to fifth steps, and fifth step.

 Hereinafter, the present invention will be described in detail.

Ketones (II) as a raw material in the first step can be easily produced from carboxylic acids and benzyl halides, for example, as shown below.

The reduction of ketones (II) is performed using a reducing agent capable of reducing ketone to alcohol.

As such a reducing agent, preferably, sodium borohydride, zinc borohydride, aluminum isopropoxide, lithium tri-tert-butoxyaluminum hydride, lithium tri-s-butylborohydride, borane, lithium aluminum hydrogen Compounds such as chloride-silica gel, alkali metal-ammonia, Raney-nickel-hydrogen and the like are used, and the amount of use is at least one equivalent or more based on the starting ketones, and is usually in the range of 1 to 10 equivalents.

This reaction is usually performed in a solvent. Examples of such a solvent include tetrahydrofuran, dioxane, ethyl ether, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, ethers such as toluene, benzene, chloroform, dichloromethane, halogenated hydrocarbons, and the like. Or a mixture of solvents inert to the reaction, such as alcohols and the like.

The reaction temperature is usually in the range of -30C to 100C, preferably in the range of -20C to 90C.

From the reaction mixture thus obtained, an alcohol (II) is obtained by operations such as liquid separation, concentration, distillation and crystallization.
Although I) can be obtained in good yield, alcohols (III) are not necessarily required to obtain esters (IV) in the next step.
Need not be isolated, and the reaction mixture may proceed to the next step.

The reaction for obtaining the esters (IV) from the alcohols (III) (second step) is carried out by reacting the alcohols (III) with an acetic acid derivative to acetylate the alcohols.

In this acetylation reaction, examples of the acetic acid derivative used include, for example, acetic anhydride, acetic chloride, and bromide.

In this reaction, the amount of the acetic acid derivative used is required to be at least 1 equivalent to the alcohol (III), and the upper limit is not particularly limited, but is preferably 4 equivalents.

This reaction is performed by using a catalyst in the presence or absence of a solvent.

When a solvent is used in this reaction, examples of the solvent include tetrahydrofuran, ethyl ether,
Acetone, methyl ethyl ketone, toluene, benzene,
An aliphatic or aromatic hydrocarbon such as chloroform, chlorobenzene, dichloromethane, dichloroethane, carbon tetrachloride, dimethylformamide, or hexane, an ether, or a solvent inert to a reaction such as a halogenated hydrocarbon is used alone or in combination. The amount used is not particularly limited.

Examples of the catalyst include dimethylaminopyridine, triethylamine, tri-n-butylamine, pyridine,
Examples thereof include organic or inorganic basic substances such as picoline, imidazole, sodium carbonate, and potassium hydrogen carbonate, and organic or inorganic acids such as toluenesulfonic acid, methanesulfonic acid, and sulfuric acid can also be used as a catalyst.

The amount of catalyst used depends on the type of lower alkyl carboxylic acids used, the combination of catalysts used, etc.
Although not necessarily specified, for example, when a halide is used as the lower alkylcarboxylic acid, the equivalent is at least 1 equivalent to the acid halide.

The reaction temperature is usually -30C to 100C, preferably -20C to 90C.

The reaction time is not particularly limited, and alcohols (II
The point at which I) disappears from the reaction system can be regarded as the reaction end point.

After completion of the reaction, usual separation means such as extraction, liquid separation,
Ester (IV) can be obtained in good yield by concentration, recrystallization, etc., which can be further purified by column chromatography or the like if necessary, but can be used as is in the reaction mixture in the next step.

Esters (IV) to optically active alcohols (V)
(Third step) is to hydrolyze one of the optically active forms of the esters using an esterase having the ability to hydrolyze one of the optically active forms of the esters (asymmetric) Water dissolution).

The microorganism that produces an esterase used in this reaction may be any microorganism that produces an esterase having the ability to asymmetrically hydrolyze esters (IV), and is not particularly limited.

In addition, the esterase in the present invention means esterase in a broad sense including lipase.

Specific examples of such microorganisms include, for example, Enterobacter, Arthrobacter, Previbacterium, Pseudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus, Lactobacillus, Trichoderma, Candida, Saccharomyces, Rhodotorula, Cryptococcus, Torulopsis, Pichia, Penicillium, Aspergillus,
Microorganisms belonging to the genera Rhizopus, Mucor, Aureobasidium, Actinomucor, Nocardia, Streptomyces, Hansenula and Achromobacter are exemplified.

The cultivation of the microorganism is generally performed according to a conventional method. For example, a culture solution can be obtained by performing liquid culture.

For example, a sterilized liquid medium [for molds and yeasts, malt extract / yeast extract medium (1 g of peptone 5 g, glucose 10 g, malt extract 3 g, yeast extract 3 g is dissolved in
6.5), and for bacteria, the microorganisms are brought into contact with a sweetened broth medium (1 g of peptone, 10 g of glucose, 5 g of meat extract, and 3 g of NaCl dissolved in 1 to pH 7.2), usually at 30 to 40 ° C.
By performing reciprocal shaking culture for 1-3 days,
Moreover, you may perform solid culture as needed.

Some of these microbial esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include, for example, the following.

Pseudomonas lipase [Lipase P (manufactured by Amano Pharmaceutical)], Aspergillus lipase [Lipase AP (manufactured by Amano Pharmaceutical)], Mucor lipase AP (manufactured by Amano Pharmaceutical), lipase of Candida syrindrasse [lipase MY (name Sugar industry)], lipase of the genus Alcaligenes [lipase PL (manufactured by Meito Sangyo)], lipase of the genus Achromobacter [lipase AL (manufactured by Meito Sangyo)], lipase of the genus Arsobacter (manufactured by Nippon Chemical), A lipase of the genus Chromobacterium (manufactured by Oriental Brewery), a lipase of Rhizopus delemar [Taripase (manufactured by Tanabe Seiyaku)], and a lipase of the genus Rhizopus [Ripase Saiken (Osaka Bacteria Research Institute)].

Also, animal and plant esterases can be used,
Specific examples of these esterases include the following.

Stearpsin, pancreatin, pig liver esterase, Wheat Germ esterase.

As the esterase used in this reaction, an enzyme obtained from an animal, a plant, or a microorganism is used, and the form of use is a purified enzyme, a crude enzyme, an enzyme-containing substance, a microorganism culture solution, a culture, a cell, a culture solution. In addition, they can be used in various forms, such as those obtained by treating them, as needed, and enzymes and microorganisms can be used in combination. Alternatively, it can be used as an immobilized enzyme immobilized on a resin or the like, or an immobilized cell.

The asymmetric hydrolysis reaction is usually carried out by vigorously stirring a mixture of the raw material esters (IV) and the above enzyme or microorganism in a buffer solution.

As the buffer, sodium phosphate which is usually used,
A buffer solution of an inorganic acid salt such as potassium phosphate, a buffer solution of an organic acid salt such as sodium acetate or sodium citrate, or the like is used, and its pH is 8 to 11 in a culture solution of an alkaliphilic bacterium or an alkaline esterase. PH 5 to 8 is preferable for a culture solution of a non-alkaline microorganism or an esterase having no alkali resistance. The concentration is usually in the range of 0.05-2M, preferably 0.05-0.5M.

The reaction temperature is usually from 10 to 60 ° C, and the reaction time is generally from 3 to 70 hours, but is not limited thereto.

After completion of the hydrolysis reaction, the hydrolysis reaction solution is extracted with a solvent such as methyl isobutyl ketone, ethyl acetate, ethyl ether, or the like, and the solvent is distilled off from the organic layer, and the concentrated residue is subjected to column chromatography. Optically active alcohols (V) as hydrolysis products and optically active esters as hydrolysis residues [optically active compounds in raw material esters (IV) which were not hydrolyzed] Can be separated.

The optically active esters obtained here may be further hydrolyzed, if necessary, to be enantiomers of the optically active alcohols (V) previously obtained.

When a lipase belonging to the genus Pseudomonas or Arthrobacter is used as the lipase in this asymmetric hydrolysis reaction, it is possible to obtain optically active alcohols with relatively high optical purity.

During the hydrolysis, toluene,
Organic solvents that are inert to the reaction, such as chloroform, methyl isobutyl ketone, and dichloromethane, can also be used.
By using these, asymmetric hydrolysis can be advantageously performed.

The reaction for obtaining the optically active ester derivative (VII) from the optically active alcohol (V) (fourth step) comprises reacting the optically active alcohol (V) with an aliphatic carboxylic acid (VI) or a derivative thereof. It is performed by

In the general formula (VI), R is an alkyl group or an alkoxyalkyl group exemplified below.

Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, 1-methylethyl, 2-methylbutyl, 2,3-dimethylbutyl, 2,3,3-trimethylbutyl, 2-methylpentyl, 3-methylpentyl, 2,3-
Dimethylpentyl, 2,4-dimethylpentyl, 2,3,3,4-
Tetramethylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 2,5-dimethylhexyl, 2-methylheptyl, 2-methyloctyl, 2-methylhexyl
Trihalomethylpentyl, 2-trihalomethylhexyl, 2-trihalomethylheptyl, 2-halopropyl,
3-halo-2-methylpropyl, 2,3-dihalopropyl, 2-halobutyl, 3-halobutyl, 2,3-dihalobutyl, 2,4-dihalobutyl, 3,4-dihalobutyl, 2-halo-3-methylbutyl, -Halo-3,3-dimethylbutyl, 2-halopentyl, 3-halopentyl, 4-halopentyl, 2,4-dihalopentyl, 2,5-dihalopentyl,
2-halo-3-methylpentyl, 2-halo-4-methylpentyl, 2-halo-3-monohalomethyl-4-methylpentyl, 2-halohexyl, 3-halohexyl, 4-
Halohexyl, 5-halohexyl, 2-haloheptyl,
2-halooctyl (however, halo in the above alkyl group represents fluorine, chlorine, bromine or iodine), methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, methoxybutyl, methoxyoctyl, methoxynonyl , Methoxydecyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, ethoxyheptyl, ethoxyoctyl, ethoxynonyl, ethoxydecyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl,
Propoxypentyl, propoxyhexyl, propoxyoctyl, propoxydecyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, butoxyheptyl, butoxynonyl, pentyloxymethyl, pentyloxyethyl, pentyloxypropyl, pentyloxy Butyl, pentyloxypentyl, pentyloxyoctyl, pentyloxydecyl, hexyloxymethyl, hexyloxyethyl, hexyloxypropyl, hexyloxybutyl, hexyloxypentyl, hexyloxyhexyl, hexyloxyoctyl, hexyloxynonyl, hexyloxydecyl , Heptyloxymethyl, heptyloxyethyl, heptyloxypropyl,
Heptyloxypentyl, octyloxymethyl, octyloxyethyl, decyloxymethyl, decyloxyethyl, decyloxypropyl.

Incidentally, these alkyl groups or alkoxyalkyl groups may be optically active groups.

Some of the optically active carboxylic acids having these optically active groups are obtained by oxidation of the corresponding alcohol and reductive deamination of the amino acid. Others can be derived from the following optically active amino acids and optically active oxyacids that are naturally occurring or obtained by resolution.

Alanine, palin, leucine, isoleucine, phenylalanine, serine, threonine, alosreonine, homoserine, alloisoleucine, tert-leucine, 2-aminobutyric acid, norvaline, norleucine, ornithine, lysine, hydroxylysine, phenylglycine, trifluoroalanine, asparagine Acid, glutamic acid, lactic acid,
Mandelic acid, tropic acid, 3-hydroxybutyric acid, malic acid, tartaric acid, isopropylmalic acid and the like.

Examples of the derivative of the aliphatic carboxylic acid represented by the general formula (VI) include an acid anhydride of an aliphatic carboxylic acid having an alkyl group or an alkoxyalkyl group described above, and an acid halide such as acid chloride and acid bromide. Is exemplified.

The reaction between the optically active alcohol (V) and the aliphatic carboxylic acid (VI) or a derivative thereof is usually carried out in the presence or absence of a solvent, generally in the presence of a catalyst.

When a solvent is used in this reaction, examples of the solvent include aliphatic solvents such as telorahydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, and hexane. Alternatively, a solvent inert to the reaction of an aromatic hydrocarbon, an ether, a halogenated hydrocarbon or the like may be used alone or in a mixture. The amount can be used without any particular limitation.

In the case of using an acid anhydride or an acid halide of the above-mentioned aliphatic carboxylic acid in the reaction, the amount of the acid anhydride to be used is at least 1 equivalent to the optically active alcohol compound (II), and the upper limit is particularly limited. Although not limited, it is preferably 4 equivalent times.

Examples of the catalyst include dimethylaminopyridine, triethylamine, tri-n-butylamine, pyridine,
Picoline, collidine, imidazole, sodium carbonate,
Organic or inorganic basic substances such as sodium methylate and potassium bicarbonate can be mentioned. Further, an organic acid or an inorganic acid such as toluenesulfonic acid, methanesulfonic acid, or sulfuric acid can be used as a catalyst.

In using such a catalyst, for example, when an acid halide of an aliphatic carboxylic acid is used as a raw material, pyridine and triethylamine are particularly preferably used.

The amount of the catalyst used depends on the type of the acid anhydride or acid halide of the aliphatic carboxylic acid and the combination of the catalyst to be used, etc., and is not necessarily specified.For example, when the acid halide is used, It is 1 equivalent times or more.

When an aliphatic carboxylic acid is used in the reaction, the carboxylic acid is usually dehydrated and condensed by using 1 to 2 equivalents of the optically active alcohol (V) in the presence of a condensing agent. An optically active benzenecarboxylic acid (I) can be obtained.

As the condensing agent, carbodiimides such as N, N'-dicyclohexylcarbodiimide and N-cyclohexyl-N '-(4-diethylamino) cyclohexylcarbodiimide are preferably used, and if necessary, organic bases such as 4-pyrrolidinopyridine, pyridine and triethylamine. Are used together.

The amount of the condensing agent to be used is 1 to 1.2 equivalent times relative to the carboxylic acid, and when a base is used, the amount to be used is 0.01 to 0.2 equivalent times to the condensing agent.

The reaction temperature is usually -30C to 100C, preferably -25C to 80C.

The reaction time is not particularly limited, and the time when the optically active alcohols (V) as the raw materials disappear can be regarded as the end point of the reaction.

After completion of the reaction, usual separation means such as extraction, liquid separation,
The optical activity represented by the general formula (VII) can be obtained from the reaction mixture by an operation such as concentration with good yield of the ester derivative, which can be purified by column chromatography or the like if necessary. The reaction mixture can be used as it is.

Reaction for obtaining desired optically active benzenecarboxylic acid from optically active ester derivative (VII) (fifth step)
Is generally carried out by subjecting an optically active ester derivative to debenzylation by catalytic hydrogenation (catalytic hydrogenation) in the presence of a catalyst.

As the catalyst, a palladium-based metal catalyst is preferably used, and specific examples thereof include palladium-carbon, palladium oxide, palladium black, and palladium chloride.

Also, nickel-based catalysts such as Raney nickel and nickel-diatomaceous earth can be used.

The amount of such a catalyst to be used is generally 0.001 to 0.5 times by weight, preferably 0.005 to 0.3 times by weight, relative to the optically active ester derivative. The reaction is usually performed in a solvent, for example, water, dioxane, tetrahydrofuran,
Inactive in reactions of aliphatic hydrocarbons such as methanol, ethanol, n-propyl alcohol, acetone, dimethylformamide, toluene, dichloromethane, and ethyl acetate, aromatic hydrocarbons, alcohols, ethers, ketones, esters, and halogenated hydrocarbons. Single or mixed portions of different solvents are used.

This reaction is carried out at a hydrogen pressure of normal pressure or under pressure, and the amount of absorbed hydrogen is an optically active ester derivative (VI
It is preferable to set the reaction end point when it becomes 1 to 1.2 equivalent times of I).

The reaction temperature ranges from -10C to 100C, preferably from 10C to 60C.

After completion of the reaction, the target optically active benzenecarboxylic acid (I) can be obtained by a method such as removing the catalyst from the reaction mixture by filtration or the like and then concentrating the same.
This can be purified by recrystallization or column chromatography if necessary.

<Effects of the Invention> Thus, according to the method of the present invention, a novel compound, an optically active benzenecarboxylic acid represented by the general formula (I), can be industrially advantageously produced, and the compound of the present invention is a liquid crystal. Not only useful as materials for
It can also be used as an intermediate for pharmaceuticals and the like.

<Example> Hereinafter, the present invention will be described with reference to examples.

Example 1 A 4′-necked flask equipped with a stirrer and a thermometer was filled with 4′-
Acetyl benzoic acid benzyl ester (II-1) 60.98 g
(0.24 mol), 100 ml of ethanol and 300 of chloroform
Then, 4.6 g (0.12 mol) of sodium borohydride is added thereto at 15 to 25 ° C. over 10 minutes.

After keeping at the same temperature for 2 hours, the reaction mixture is poured into ice water and extracted twice with 200 ml of ethyl acetate. The organic layer is washed with water and concentrated under reduced pressure to give 4- (1-hydroxyethyl) phenylcarboxylic acid benzyl ester (III-
1) 58.37 g (95% yield) was obtained. ▲ n ²⁵ _D ▼ 1.5682 Next, 55.90 g (0.22 mol) of (III-1) obtained above was dissolved in a mixed solution consisting of 300 ml of toluene and 100 ml of pyridine, and 18.48 g (0.24 mol) of acetyl chloride was added thereto. ~ 20
Add over 2 hours at ° C. 1 hour at the same temperature, 30-35
Incubate at ° C for 2 hours. After completion of the reaction, the reaction mixture is cooled to 10 ° C. or lower, and thereto is added 3N-hydrochloric acid aqueous solution (600 ml). The organic layer was concentrated under reduced pressure, and further purified by column chromatography to obtain 4- (1
-Acetoxyethyl) phenylcarboxylic acid benzyl ester (IV-1) (32.15 g, yield 98%) was obtained.

▲ n ²⁵ _D ▼ 1.5304 29.81 g (0.1 mol) of (IV-1) obtained above was mixed with 600 ml of 0.1 M phosphate buffer (pH 7.0), 15 ml of chloroform and 6 g of amanolipase “P”, and the mixture was mixed with 40 to 45 g. Stir vigorously for 20 hours at ° C.

After completion of the reaction, the reaction mixture was washed with methyl isobutyl ketone 90
Extract with 0ml. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a mixture of hexane: ethyl acetate = 12: 1 as an eluent to give (+)-4- (1-hydroxyethyl) phenylcarboxylic acid benzyl ester. (V-1) 11.21 g [▲ [α] ²⁰ _D ▼ + 35.6 ゜ (c = 1, CHC
l ₃ ), ▲ n ²⁵ _D ▼ 1.5694] and (−)-4 ′-(1-
15.96 g of acetoxyethyl) -4-phenylcarboxylic acid benzyl ester [▲ [α] ²⁵ _D ▼ -52 ゜ (c = 1, CHC
l ₃ ), ▲ n ²⁵ _D ▼ 1.5293].

Next, 1.02 g (4 mmol) of (V-1) obtained here,
To a mixed solution of 5 ml of pyridine and 10 ml of toluene, 0.66 g (4.4 mmol) of hexanoic acid chloride is added dropwise at 15 to 20 ° C. Thereafter, the reaction is continued at 20 ° C for 2 hours and at 40 to 50 ° C for 2 hours. After the reaction is complete, pour the reaction solution into ice water and add toluene
Extract with 30ml. The toluene layer is 1N-hydrochloric acid aqueous solution, 2
Wash successively with aqueous sodium bicarbonate and water. The organic layer is dried with anhydrous magnesium sulfate.

This toluene layer is concentrated under reduced pressure, and the residue is further subjected to silica gel column chromatography (elution solvent: toluene).
Purify with. (+)-4- (1-hydroxyethyl)
1.39 g (98% yield) of hexanoic acid ester (VII-1) of benzyl phenylcarbalbonate was obtained.

▲ [α] ²⁵ _D ▼ + 49.2 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5221 Next, 1.06 g (3 mmol) of (VII-1) obtained here was added to 10 ml of tetrahydrofuran and 5% Pd -Mix with 0.1 g of carbon and hydrogenate the catalyst at normal pressure in a hydrogen atmosphere. The reaction is stopped when the hydrogen absorption is equimolar, and the catalyst is removed separately. The liquid was concentrated, and the residue was purified by column chromatography to obtain 0.75 g of (+)-4- (1'-hexanoyloxyethyl) benzoic acid (95% yield).

▲ [α] ²⁵ _D ▼ + 68.8 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.4849 Example 2 (−)-4 ′-(1-acetoxyethyl) -4-obtained in Example 1 10 g of phenylcarboxylic acid benzyl ester
Mix with 200 ml of 0.2 M phosphate buffer, 5 ml of chloroform and 1 g of Amanobata liver esterase and vigorously stir at 30-35 ° C. for 30 hours.

Thereafter, post-treatment and purification were performed in the same manner as in Example 1, and (-)
7.7 g of 4- (1-hydroxyethyl) phenylcarboxylic acid benzyl ester (V-2) was obtained.

Next, 1.02 g (4 mmol) of (V-2) obtained here, 2
In a solution of 0.49 g (4.8 mmol) of S-2-methylbutanoic acid and 20 ml of dichloromethane, 0.91 g (4.4 mmol) of dicyclohexylcarbodiimide and 0.02 g of 4-pyrrolidinopyridine are added and reacted at room temperature for 12 hours. After completion of the reaction, the precipitated crystals are separately removed and the solution is concentrated. The residue is purified by column chromatography as in Example 1. 1.29 g (yield: 95.0%) of 2S-2-methylbutanoic acid ester (VII-2) of benzyl (-)-4- (1-hydroxyethyl) phenylcarboxylate was obtained.

▲ [α] ²⁵ _D ▼ 55.2 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5295 Next, 1.02 g (3 mmol) of (VII-2) obtained here was treated with 30 ml of ethyl acetate and 2% Pd- It is mixed with 0.1 g of carbon and contact hydrogenated at normal pressure in a hydrogen atmosphere.

Thereafter, post-treatment and purification were carried out in the same manner as in Example 1.
(-)-4- (2S-2-methylbutyryloxyethyl)
0.72 g (96% yield) of benzoic acid was obtained.

▲ [α] ²⁵ _D ▼ -74 ° C. (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5013 Example 3 (+)-4- (1-hydroxyethyl) phenylcarboxylic acid benzyl ester obtained in Example 1 (V-1) 1.
02 g (4 mmol) was dissolved in a mixed solution consisting of 10 ml of dichloroethane and 10 ml of pyridine.
Add 0.76 g (4.4 mmol) and react at 20-25 ° C for 15 hours. After completion of the reaction, the reaction mixture is poured into ice, and extracted with 20 ml of dichloroethane. Thereafter, post-treatment and purification were carried out in the same manner as in Example 1 to obtain 1.27 g (yield 97%) of butyric acid ester (VII-3) of benzyl (+)-4- (1-hydroxyethyl) phenylcarboxylate. Was.

▲ [α] ²⁵ _D ▼ + 51.5 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5243 Next, 0.98 g (3 mmol) of (VII-3) obtained here was added to 10 ml of tetrahydrofuran, 3 ml of ethanol and It is mixed with 0.05 g of palladium oxide and contact hydrogenated at normal pressure in a hydrogen atmosphere. Thereafter, post-treatment and purification were carried out in the same manner as in Example 1 to obtain 0.68 g (yield 96%) of (+)-4- (1-butyryloxyethyl) benzoic acid.

▲ [α] ²⁵ _D ▼ + 94.2 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5138 Example 4 4′- placed in a four-necked flask equipped with a stirrer and a thermometer.
32.17 g (0.12 mol) of methyl benzyl acetylphenylcarboxylate (II-4), 50 ml of ethanol, 100 ml of dichloromethane and 50 ml of tetrahydrofuran were charged, and 2.3 g of sodium borohydride was added thereto at 15 to 25 ° C.
(0.06 mol) is added over 10 minutes.

After keeping the mixture at the same temperature for 2 hours, the reaction mixture was poured into ice water, and post-treated in the same manner as in Example 1 to give 31.43 g of 4- (1-hydroxyethyl) phenylcarboxylic acid methylbenzyl ester (III-4) (III-4). 97%).

Next, 29.71 g (0.11 mol) of the obtained (III-4) was dissolved in a mixture of 200 ml of dichloromethane and 50 ml of pyridine, and 50 ml of a dichloromethane solution containing 9.42 g (0.12 mol) of acetyl chloride was added to the mixture. Add at 25 ° C.

Thereafter, the temperature is kept at 20 to 25 ° C for 2 hours. After the reaction,
After cooling to 10 ° C. or less, 300 ml of 3N-hydrochloric acid solution is added, and the organic layer is separated, and washed with water, 7% water in a heavy tank and water in this order. After drying over anhydrous magnesium sulfate, the organic layer was concentrated and 33.3 g of 4- (1- (acetoxyethyl) phenylcarboxylic acid methylbenzyl ester (IV-4) as a pale yellow oil was obtained.
(97% yield).

15.6 g (50 mmol) of (IV-4) obtained above was mixed with 200 ml of 0.3 M phosphate buffer (pH 7.0), 10 ml of chloroform and 3 g of amanolipase "P", and the mixture was vigorously stirred at 38 to 40 ° C for 24 hours. I do.

After completion of the reaction, the reaction mixture is extracted with 600 ml of ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a mixture of hexane: ethyl acetate = 12: 1 as an eluent, and methylbenzyl (+)-4- (1-hydroxyethyl) phenylcarboxylate was purified. Esters (V-
4) 5.95 g [▲ [α] ²⁵ _D ▼ + 36.3 ゜ (c = 1, CHCl ₃ ),
{N ²⁰ _D ▼ 1.5688] was obtained.

Next, 1.08 g (4 mmol) of (V-4) obtained here,
0.91 g (0.480 mmol) of decanoic chloride is added dropwise to a mixed solution of 5 ml of pyridine and 10 ml of toluene at 20 ° C.
Thereafter, the reaction is continued at 20 ° C for 10 hours and at 40 to 45 ° C for 2 hours. Hereinafter, after-treatment and purification according to Example 1,
Decanoic acid ester of methylbenzyl (+)-4- (1-hydroxyethyl) phenylcarboxylate (VII-4) 1.6
0 g (yield 94.5%) was obtained.

▲ [α] ²⁵ _D ▼ + 44.5 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5172 Next, 1.27 g (3 mmol) of (VII-4) obtained here was used to prepare Example 1 The reaction mixture was subjected to catalytic hydrogenation under the same conditions, followed by post-treatment and purification to obtain (+)-4- (1-decanoyloxyethyl) benzoic acid in a yield of 95.5%.

▲ [α] ²⁵ _D ▼ + 62 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.4810 Example 5 4′-acetylphenyl carboxylic acid instead of 4′-acetylphenyl carboxylic acid methylbenzyl ester (II-4) 34.09 g of acid methoxybenzyl ester (II-5) (0.
The same result as in Example 4 was obtained by reduction, acetylation and asymmetric hydrolysis except that 12 mol) was used as a raw material.

4- (1-hydroxyethyl) phenylcarboxylic acid methoxybenzyl ester (III-5) yield 96.5% 4- (1-acetoxyethyl) phenylcarboxylic acid methoxybenzyl ester (IV-5) yield 96.3% (+)- 2.34 g of 4- (1-hydroxyethyl) phenylcarboxylic acid methoxybenzyl ester (V-5) ▲ [α] ²⁵ _D ▼ + 37.0 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5724 1.14 g (4 mmol) of (V-5) obtained in
Palmitic acid chloride is added dropwise to a mixed solution of 10 ml of pyridine and 5 ml of toluene. Then, it is made to react at 25-30 degreeC for 10 hours.

Hereinafter, post-treatment and purification are performed according to Example 1.
(+)-4- (1-hydroxyethyl (palmitic acid ester of methoxybenzyl phenylcarboxylate (VII-
5) 1.91 g (90% yield) was obtained.

▲ [α] ²⁵ _D ▼ + 36 ゜ (c = 1, CHCl ₃ ) Next, 1.48 g (3 mmol) of (VII-5) obtained here was mixed with 20 ml of ethyl acetate and 0.3 g of 5% Pd-carbon. And hydrogenation at normal pressure in a hydrogen atmosphere. The reaction is stopped when the hydrogen absorption is equimolar, and the catalyst is removed separately. The liquid was concentrated, and the residue was purified by column chromatography to obtain (+)-4- (1-palmitoyloxyethyl) benzoic acid 1.17 g (yield 97%).

▲ [α] ²⁵ _D ▼ + 54 ° (c = 1, CHCl ₃ ) waxy solid Example 6 (−)-4- (1-hydroxyethyl) phenylcarboxylic acid benzyl ester (V-2) ) -4
1.02 g (4 mmol) of-(1-hydroxyethyl) phenylcarboxylic acid benzyl ester (V-1) was added to (2S, 3
S) 2S- in place of 2-chloro-3-methylpentanoic acid
Example 2 except that 4.8 mmol of methylbutanoic acid was used
The acylation reaction, post-treatment and purification according to (+)-
2-S-methylbutanoic acid ester of benzyl 4- (1-hydroxyethyl) phenylcarboxylate (VII-6) was obtained in a yield of 9
Obtained at 5.5%.

▲ [α] ²⁵ _D ▼ + 67.6 ゜ (c = 1, CHCl ₃ ), ▲ n ²⁵ _D ▼ 1.5302 Next, an example was carried out using 1.05 g (3 mmol) of (VII-6) obtained here. Catalytic hydrogenation reaction, post-treatment and purification were carried out according to 1 to obtain 0.72 g (yield 96.5%) of (+)-4- (2S-methylbutyryloxyethyl) benzoic acid.

▲ [α] ²⁵ _D ▼ + 51 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.4821 Example 7 4′- was placed in a four-necked flask equipped with a stirrer and a thermometer.
33.0 g (0.10 mol) of acetyl-4-biphenylcarboxylic acid zendyl ester (II-7), 50 ml of ethanol and 200 ml of tetrahydrofuran were charged, and 3.8 g (0.10 mol) of sodium borohydride was added thereto at 15 to 25 ° C. for 10 minutes. And add it.

After keeping the mixture at the same temperature for 2 hours, the reaction mixture is poured into ice water and extracted twice with 300 ml of chloroform. The organic layer was washed with water and concentrated under reduced pressure to obtain 32.9 g (yield: 99%) of benzyl 4- (1-hydroxyethyl) -4-biphenylcarboxylate (III-7).

Next, 29.9 g (0.09 mol) of the obtained (III-7) was dissolved in a mixed solution consisting of 150 ml of toluene and 50 ml of pyridine, and 9.42 g (0.12 mol) of acetyl chloride was added to 15 to 2 g.
Add over 2 hours at 0 ° C. 2 hours at the same temperature, 40 ~ 4
Incubate at 5 ° C for 2 hours. After the completion of the reaction, the reaction mixture is cooled to 10 ° C. or lower, and thereto is added 3N-hydrochloric acid solution (300 ml). The organic layer was concentrated under reduced pressure, and further purified by column chromatography to obtain 4'-
33.0 g (98% yield) of (1-acetoxyethyl) -4-biphenylcarboxylic acid benzyl ester (IV-7) was obtained. 29.9 g (0.80 mol) of (IV-7) obtained above was mixed with 800 ml of 0.1 M phosphate buffer (pH 7.5), 30 ml of chloroform and 6 g of amanolipase "P", and stirred vigorously at 30 to 35 ° C for 20 hours. I do.

After completion of the reaction, the reaction mixture was treated with methyl isobutyl ketone 60
Extract with 0ml. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a mixture of chloroform: ethyl acetate = 12: 1 as an eluent to give (+)-4 '-(1
-Hydroxyethyl) -4-biphenylcarboxylic acid benzyl ester (V-7) 10.6 g (melting point 108-110.5 ° C) and (-)-4 '-(1-acetoxyethyl) -4-biphenylcarboxylic acid benzyl ester 17.5 g I got

1.00 g (3 mmol) of (V-7) obtained here, 10 ml of pyridine, 10 ml of toluene and 0.77 g of hexanoic anhydride
(3.6 mmol) is reacted for 15 hours at 20-25 ° C. After the reaction is completed, pour the reaction solution into ice water and 30 ml of toluene.
Perform extraction processing. The toluene layer is sequentially washed with 1N aqueous hydrochloric acid, 2% aqueous sodium bicarbonate and water.

The toluene layer is concentrated under reduced pressure, and the residue is further purified by silica gel column chromatography. (+)
Hexanoic acid ester of benzyl-4 '-(1-hydroxyethyl) -4-biphenylcarboxylate (VII-7) 1.2
4 g (96% yield) were obtained.

▲ [α] ²⁵ _D ▼ +46.5 (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5480 Next, 0.86 g (2 mmol) of (VII-7) obtained above, 30 ml of tetrahydrofuran and 5% Pd- A mixture of 0.19 g of carbon was subjected to catalytic hydrogenation, post-treatment and purification in the same manner as in Example 1 to give (+)-4 '-(1-hexanoyloxyethyl).
0.64 g (95% yield) of -4-carboxy-biphenyl was obtained.

▲ [α] ²⁵ _D ▼ + 69 ゜ (c = 1, CHCl ₃ ) Melting point 133-135 ° C. Example 8 (−)-4 ′-(1-acetoxyethyl) -4-biphenylcarboxylic acid obtained in Example 7 Benzyl ester 15
g, chloroform 10 ml, 0.2 M phosphate buffer 400 ml and Amanobata liver esterase 3 g, and mix at 30-35 ° C. for 30 minutes.
Stir for hours. After completion of the reaction, the reaction mixture was extracted with chloroform and separated, the chloroform layer was concentrated, and the residue was purified by column chromatography to give (-)-4 '-(1-hydroxyethyl) -4-. 11.8 g of biphenylcarboxylic acid benzyl ester (V-8) was obtained.

Next, 1.00 g (3 mmol) of (V-8), 15 ml of dichloromethane, 0.37 g (3.6 mmol) of 2S-methylbutanoic acid,
3.3 mmol of dicyclohexcarbodiimide and 4-
A mixture of 0.02 g of pyrrolidinopyridine is reacted at 20-25 ° C. for 12 hours. After separating insolubles, the liquid was concentrated, and the residue was purified by column chromatography to give (-)-4'-.
2S-methylbutanoic acid ester of benzyl (1-hydroxyethyl) -4-biphenylcarboxylate (VII-8) was obtained in a yield of 95%.

▲ [α] ²⁵ _D ▼ -63 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5564 Next, 0.83 g (2 mmol) of (VII-8), 10 ml of tetrahydrofuran, 2 ml of methanol and 5% Pd-carbon 0.17g
Is subjected to a catalytic hydrogenation reaction under normal pressure. After the reaction,
The catalyst was separated, and after-treatment and purification were conducted in the same manner as in Example 7 to obtain 0.62 g of (-)-4 '-(1-2S-methylbutanoyloxyethyl) -4-carboxybiphenyl (yield 95.
5%). ▲ [α] ²⁰ _D ▼ -77 ° C (c = 1, CHCl ₃ ),
Melting point: 161 ° C. Example 9 4′- placed in a four-necked flask equipped with a stirrer and a thermometer.
Acetyl-4-biphenylcarboxylic acid p-chlorobenzyl ester (II-9) 36.5 g (0.10 mol), ethanol 5
0 ml and 150 ml of chloroform, and add 15 to 25 ° C
Then, 3.8 g (0.10 mol) of sodium borohydride is added over 10 minutes.

After keeping at the same temperature for 2 hours, the reaction mixture is poured into ice water and extracted twice with 200 ml of ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure to obtain 36.5 g (yield 99.5%) of p-chlorobenzyl 4- (1-hydroxyethyl) -4-biphenylcarboxylate (III-9).

Next, 33.0 g (0.09 mol) of the obtained (III-9) was dissolved in 150 ml of toluene and 50 ml of pyridine, and 9.42 g (0.12 mol) of acetyl chloride was required at 15 to 20 ° C for 2 hours. And add. Then, at the same temperature for 1 hour, 40-50 ℃
The reaction is continued for 2 hours. After completion of the reaction, the reaction solution is poured into ice water and extracted with 50 ml of toluene. The toluene layer is
Wash sequentially with 3N aqueous hydrochloric acid, 5% aqueous sodium bicarbonate and water.

The toluene layer is concentrated under reduced pressure, and the residue is further purified by silica gel column chromatography. 4'-
36.4 g of (1-acetoxyethyl) -4-biphenylcarboxylic acid p-chlorobenzyl ester (IV-9) (yield 99.
0%). 32.7 g (0.08 mol) of (IV-9) obtained above
800 ml of 0.1 M phosphate buffer (pH 7.5), 30 ml of chloroform
And 6 g of Amano lipase “P” and mix at 40-45 ° C. for 20 minutes.
Stir vigorously for hours.

After completion of the reaction, the reaction mixture was treated with methyl isobutyl ketone 60
Extract with 0ml. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a mixture of hexane: ethyl acetate = 12: 1 as an eluent to give (+)-4 '-(1-hydroxyethyl) -4-biphenyl. 13.8 g of [p-chlorobenzyl carboxylate (V-9) [▲ [α] ²⁵ _D ▼ + 21.7 ° (c = 0.544, CHCl ₃ ), melting point 108-110.5 ° C.] was obtained.

Next, to a mixed solution of 1.0 g (3 mmol) of (V-9) obtained above, 10 ml of pyridine and 10 ml of dichloromethane, 0.31 g (3.3 mmol) of propionyl chloride is added dropwise at 20 to 25 ° C. Thereafter, the reaction is carried out at 25 ° C for 3 hours and at 40 to 45 ° C for 3 hours. Thereafter, post-treatment and purification were carried out according to Example 7 to give (+)-4 '-(1-hydroxyethyl) -4-.
1.12 g (97% yield) of p-chlorobenzyl biphenylcarboxylate propionate (VII-9) was obtained.

▲ [α] ²⁵ _D ▼ + 28 ゜ (c = 1, CHCl ₃ ) Next, 0.78 g (2 mmol) of (VII-9) was mixed with tetrahydrofuran and 0.1 g of 5% Pd-carbon, and the mixture was constantly added in a hydrogen atmosphere. Contact hydrogenation with pressure. Thereafter, post-treatment and purification were conducted in the same manner as in Example 1 to obtain 0.58 g (yield 96.5%) of (+)-4 '-(1-propionyloxyethyl) -4-carboxybiphenyl. ▲ [α] ²⁵ _D ▼ + 89 ゜ (c = 1, CHC
l ₃ ), melting point 175-176 ° C. Examples 10-12 Example 2 except that the carboxylic acid (4.8 mmol) shown in Table 1 was used instead of (2S, 3S) -2-chloro-3-methylpentanoic acid. Acylation and catalytic hydrogenation were carried out according to the procedures shown in Table 1 to obtain the results shown in Table 1.

Examples 13 to 14 The carboxylic acids shown in Table 2 in place of 2S-methylbutanoic acid 3.
Acylation and catalytic hydrogenation were carried out according to Example 8, except that 6 mmol was used, and the results shown in Table 2 were obtained.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication location C07B 61/00 300 C07B 61/00 300 C07M 7:00

Claims (5)

(57) [Claims] 1. A compound of the general formula (VII) (Wherein, R represents an alkyl group or an alkoxyalkyl group which may contain a halogen atom having 1 to 20 carbon atoms,
R 'represents a lower alkyl group, a lower alkoxyl group or a benzyl group which may be substituted with a halogen atom;
Is 1 or 1, and * represents an asymmetric carbon atom. Wherein the optically active ester derivative of formula (I) is debenzylated by catalytic hydrogenation. (In the formula, R, n and * have the same meanings as described above.) A process for producing optically active benzenecarboxylic acids represented by the formula: 2. The formula (V) (In the formula, R ′ represents a lower alkyl group, a lower alkoxyl group or a benzyl group which may be substituted with a halogen atom, n is 1 or 2, and an asterisk (*) indicates an asymmetric carbon atom. An optically active alcohol represented by the general formula (VI) R-COOH (VI) (wherein R represents an alkyl group or an alkoxyalkyl group which may contain a halogen atom having 1 to 2 carbon atoms) ) To obtain an optically active ester derivative represented by the general formula (VII), followed by catalytic dehydrogenation of the derivative to carry out debenzylation. A method for producing an optically active benzenecarboxylic acid represented by the general formula (I): 3. A compound of the general formula (IV) (Wherein R ′ represents a lower alkyl group, a lower alkoxyl group or a benzyl group optionally substituted with a halogen atom, R ″ represents a methyl group, and n is 1 or 2). Is asymmetrically hydrolyzed using an esterase having the ability to preferentially hydrolyze one of the optically active forms of the esters to obtain an optically active alcohol represented by the general formula (V). Then, the optically active alcohol is reacted with an aliphatic carboxylic acid represented by the general formula (VI) or a derivative thereof to obtain an optically active ester derivative represented by the general formula (VII). A process for producing an optically active benzenecarboxylic acid represented by the general formula (I), wherein debenzylation is carried out by hydrogenation. 4. A compound of the general formula (III) (In the formula, R ′ represents a lower alkyl group, a lower alkoxyl group or a benzyl group optionally substituted with a halogen atom, and n is 1 or 2). To obtain an ester represented by the general formula (IV), followed by asymmetric hydrolysis using an esterase having an ability to preferentially hydrolyze one of the optically active isomers of the ester, to obtain a compound of the general formula Obtaining an optically active alcohol represented by the formula (V), and then converting the optically active alcohol to a compound of the general formula (VI)
To obtain an optically active ester derivative represented by the general formula (VII), followed by catalytic hydrogenation of the derivative to debenzylate. A method for producing an optically active benzenecarboxylic acid represented by the general formula (I). 5. A compound of the general formula (II) (Wherein R ′ represents a lower alkyl group, a lower alkoxyl group or a benzyl group which may be substituted with a halogen atom, and n is 1 or 2). To obtain an alcohol represented by the general formula (III), and then react the alcohol with an acetic acid derivative to obtain an ester represented by the general formula (IV). Asymmetric hydrolysis using an esterase having the ability to preferentially hydrolyze any one of the above, to obtain an optically active alcohol represented by the general formula (V). Reaction with an aliphatic carboxylic acid represented by the general formula (VI) or a derivative thereof to obtain an optically active ester derivative represented by the general formula (VII), followed by catalytic hydrogenation of the derivative to remove the derivative. Process for producing an optically active benzene carboxylic acids represented by the general formula (I), characterized in that the Njiru of.